title: Examining the overlap between genome-wide rare variant association signals and linkage peaks in rheumatoid arthritis.
abstract: OBJECTIVE
  With the exception of the major histocompatibility complex (MHC) and STAT4, no other rheumatoid arthritis (RA) linkage peak has been successfully fine-mapped to date. This apparent failure to identify association under peaks of linkage could be ascribed to the examination of common variation, when linkage is likely to be driven by rare variants. The purpose of this study was to investigate the overlap between genome-wide rare variant RA association signals observed in the Wellcome Trust Case Control Consortium (WTCCC) study and 11 replicating RA linkage peaks, defined as regions with evidence for linkage in >1 study.
  
  
  METHODS
  The WTCCC data set contained 40,482 variants with minor allele frequency of ≤0.05 in 1,860 RA patients and 2,938 controls. Genotypes of all rare variants within a given gene region were collapsed into a single locus and a global P value was calculated per gene.
  
  
  RESULTS
  The distribution of rare variant signals (association P≤10(-5)) was found to differ significantly between regions with and without linkage evidence (P=2×10(-17) by Fisher's exact test). No significant difference was observed after data from the MHC region were removed or when the effect of the HLA-DRB1 locus was accounted for.
  
  
  CONCLUSIONS
  The results suggest that rare variant association signals are significantly overrepresented under linkage peaks in RA, but the effect is driven by the MHC. This is the first study to examine the overlap between linkage peaks and rare variant association signals genome-wide in a complex disease.
authors.affiliation: University of Manchester, Manchester, UK.
authors.forename: S
authors.initials: S
authors.lastname: Eyre
authors.forename: X
authors.initials: X
authors.lastname: Ke
authors.forename: R
authors.initials: R
authors.lastname: Lawrence
authors.forename: J
authors.initials: J
authors.lastname: Bowes
authors.forename: K
authors.initials: K
authors.lastname: Panoutsopoulou
authors.forename: A
authors.initials: A
authors.lastname: Barton
authors.forename: W
authors.initials: W
authors.lastname: Thomson
authors.forename: J
authors.initials: J
authors.lastname: Worthington
authors.forename: E
authors.initials: E
authors.lastname: Zeggini
mesh_terms: D000328:Adult; D001172:Arthritis, Rheumatoid / Q000235:genetics*; D016022:Case-Control Studies; D015331:Cohort Studies; D008040:Genetic Linkage; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006684:HLA-DR Antigens / Q000235:genetics; D059811:HLA-DRB1 Chains; D006801:Humans; D008285:Major Histocompatibility Complex / Q000235:genetics; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D006113:United Kingdom / Q000453:epidemiology; D055815:Young Adult
chemical_list: D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains